EP2084174B1 - Preparation of nucleosides ribofuranosyl pyrimidines - Google Patents

Preparation of nucleosides ribofuranosyl pyrimidines Download PDF

Info

Publication number
EP2084174B1
EP2084174B1 EP07839369.1A EP07839369A EP2084174B1 EP 2084174 B1 EP2084174 B1 EP 2084174B1 EP 07839369 A EP07839369 A EP 07839369A EP 2084174 B1 EP2084174 B1 EP 2084174B1
Authority
EP
European Patent Office
Prior art keywords
formula
aryl
methyl
process according
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP07839369.1A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2084174A1 (en
Inventor
Steven D. Axt
Keshab Sarma
Justin Vitale
Jiang Zhu
Bruce Ross
Suguna Rachakonda
Qingwu Jin
Byoung-Kwon Chun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Gilead Pharmasset LLC
Original Assignee
F Hoffmann La Roche AG
Gilead Pharmasset LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Gilead Pharmasset LLC filed Critical F Hoffmann La Roche AG
Priority to PL07839369T priority Critical patent/PL2084174T3/pl
Priority to SI200731311T priority patent/SI2084174T1/sl
Publication of EP2084174A1 publication Critical patent/EP2084174A1/en
Application granted granted Critical
Publication of EP2084174B1 publication Critical patent/EP2084174B1/en
Priority to CY20131100912T priority patent/CY1114666T1/el
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • the present invention relates to an improved process for the preparation of 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one of the formula which is a potent inhibitor of Hepatitis C Virus (HCV) NS5B polymerase.
  • HCV Hepatitis C Virus
  • An object of the present invention is to provide an improved and scalable process for the preparation of 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one of the formula which avoids the drawbacks known in the art.
  • the process of the present invention comprises
  • (aryl)alkanoic acid refers to a group RCO 2 H wherein R is either alkyl or aryl as those terms are defined herein.
  • (aryl)alkanoic ester refers to a group RCO 2 R' where R is either alkyl or aryl. Most typically the R' represents the 3' and/or 5' position(s) of a ribose ring.
  • (aryl)alkanoyl” and “(aryl)alkanoyloxy” refer to the groups RCO- and RCOO- respectively, where R is as described previously.
  • (aryl)alkanoyloxymethyl refers a group RCOOCH2- where R is as described previously.
  • alkyl denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
  • aryl refers to phenyl group.
  • R has the meaning of phenyl.
  • the transformation in step a) comprises a reduction in the presence of a reducing agent and a subsequent chlorination in the presence of chlorinating agent.
  • Suitable reducing agent is sodium bis -(2-methoxyethoxy) (2,2,2-trifluoroethoxy) aluminum hydride which is commercially available under the tradename RedAl® as a solution in toluene.
  • the reduction usually takes place in an organic solvent such as in a halogenated hydrocarbon like dichloromethane at a reaction temperature of below 0°C, preferably below -5°C.
  • reaction mixture After completion of the reduction the reaction mixture is subjected to the chlorination reaction.
  • the chlorinating agent is as a rule selected from sulfuryl chloride, thionyl chloride or phosphorus oxychloride.
  • sulfuryl chloride in the presence of catalytic amounts oftetrabutyl ammonium bromide is used.
  • the chlorination is expediently performed at a reaction temperature between 0°C and 40°C.
  • the conversion in step b) comprises reacting the (aryl)alkanoic acid (2R,3R,4R)-2-(aryl)alkanoyloxy methyl-5-chloro-4-fluoro-4-methyl-tetrahydro-furan-3-yl ester of formula III with O-trimethyl silyl-N4-benzoylcytosin in the presence of a Lewis acid.
  • the O-trimethyl silyl-N4-benzoylcytosin may be prepared in situ by reacting N-benzoyl cytosine with hexamethyldisilazan in the presence of ammonium sulfate in chlorobenzene under reflux conditions.
  • the reaction is usually performed at elevated temperature, for instance at about 70°C until the coupling is complete.
  • step c) The hydrolysis in step c) is performed in the presence of a base.
  • Suitable bases are organic bases like alkali metal alkoxides. Preferably sodium methoxide in methanol as solvent is used.
  • the reaction is performed at elevated temperature, for instance at about 50°C until the hydrolysis is complete.
  • the process comprises the steps
  • step a1) The asymmetric hydroxylation in step a1) was discovered to be best carried out with sodium permanganate in the presence of ethylene glycol, sodium bicarbonate in acetone at a temperature of -20 to 0° C which afforded the diol in 60-64% on pilot plant scale.
  • Starting compound (V) can be obtained from (1S,2S)-1,2- bis -((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethane-1,2-diol ( C. R. Schmid and J. D. Bryant, Jerry D., Org. Syn. 1995 72:6-13 ) by oxidative cleavage of the diol and treating the resulting aldehyde with 2-(triphenyl- ⁇ 5 -phosphanylidene)-propionic acid ethyl ester.
  • the cyclic sulfate (VIII) can be prepared by cyclization of the vicinal diol with e.g. thionyl chloride in step b1) and oxidation of the resulting cyclic sulfite (VII) in step c1) to the corresponding sulfate (VIII) with NaOCl in the presence ofMeCN. It has been found that the cyclic sulfates can be stabilized during processing by the addition of a trialkylamine such as TEA or DIPEA at 2-10 mole % relative to the cyclic sulfate.
  • a trialkylamine such as TEA or DIPEA
  • DSC Differential scanning calorimetry
  • R phenyl
  • other potential protecting groups selected from methoxymethyl, methoxyethyl, benzyloxymethyl, ethoxymethyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acyl including acetyl, pivaloyl, benzoyl, toluoyl, 4-phenyl benzoyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, other substituted benzoyl may be applied.
  • the base used for step f1) includes, but is not limited to the following list: imidazole, pyridine, DMAP, TEA, DIPEA, 1,4-diazabicyclo[2,2,2]octane.
  • the solvent used for step f1) includes, but is not limited to acetonitrile, pyridine, DCM, chloroform, DCE, THF.
  • the abbreviations used include: 1,2-dichloroethane (DCE), dichloromethane (DCM), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), ethanol (EtOH), ethylacetate (EtOAc), methanol (MeOH), methyl (Me), ethyl (Et), isopropanol (IPA), acetonitrile (MeCN), phenyl (Ph), room temperature (rt or RT), triethylamine (TEA or Et 3 N), tetrahydrofuran (THF).
  • DCE 1,2-dichloroethane
  • DCM dichloromethane
  • DIPEA di-iso-propylethylamine
  • DMA N,N-dimethyl acetamide
  • DMAP 4-N,N-dimethylamino
  • Benzoic acid 3-benzoyloxy-5-(4-benzoylamino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl ester (XIII).
  • Trifluoroethanol (4.08 kg) is added slowly to a cold solution (-15°C) of RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at or below -10°C. After warming up to ambient temperature (ca.
  • the modified RED-AL® reagent mixtuer (30.1 kg out of the 37.6 kg prepared) is added slowly to a pre-cooled solution (-15 °C) of fluorolactone dibenzoate XI (10 kg) in DCM (94.7 kg) while maintaining reaction temperature at or below -10 °C.
  • a pre-cooled solution 15 °C
  • fluorolactone dibenzoate XI 10 kg
  • DCM 94.7 kg
  • catalytic amounts of tetrabutylammonium bromide (90 g) is added to the reaction mixture.
  • Sulfuryl chloride (11.86 kg) is then added while maintaining reaction temperature at or below 0°C.
  • the reaction mixture is then heated to 40°C until formation of the chloride is complete (ca.
  • a suspension ofN-benzoyl cytosine (8.85 kg), ammonium sulfate (0.07 kg) and hexamethyldisilazane (6.6 kg) in chlorobenzene (52.4 kg) is heated to reflux (ca. 135°C) and stirred (ca. 1 h) until the mixture becomes a clear solution.
  • the reaction mixture is then concentrated in vacuo to obtain the O-trimethyl silyl-N4-benzoylcytosin as a syrupy liquid.
  • the anhydrous solution of 30 in chlorobenzene (as prepared) and stannic chloride (282 kg) are added to this concentrate.
  • the reaction mixture is maintained at about 70°C until the desired coupling reaction is complete (ca.
  • the combined filtrate is concentrated under atmospheric pressure (the distillate collected in the process is used for reslurrying the filter cake) until the batch temperature rises to about 90°C and then allowed to cool slowly to about -5°C.
  • the resulting slurry is aged for at least 2 h at -5°C.
  • a slurry of XIII (14.7 kg) in MeOH (92.6 kg) is treated with catalytic amounts of methanolic sodium methoxide (0.275 kg).
  • the reaction mixture is heated to ca. 50°C and aged (ca. 1 h) until the hydrolysis is complete.
  • the reaction mixture is quenched by addition of isoburyric acid (0.115 kg).
  • the resulting solution is concentrated under moderate vacuum and then residual solvents are replaced with IPA (80 kg).
  • the batch is distilled to a volume of ca. 50 L.
  • the resulting slurry is heated to ca. 80°C and then cooled slowly to ca. 5°C and aged (ca. 2 h).
  • the precipitated product is isolated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70°C in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure
  • a suspension of V (10 kg, CAS Reg. No. 81997-76-4), ethylene glycol (11.6 kg), solid NaHCO 3 (11.8 kg) and acetone (150 L) is cooled to ca. -15 °C.
  • a solution of 36% aqueous NaMnO4 (19.5 kg) is charged slowly (over 4 h) to the suspension maintaining reaction temperature at or below -10°C.
  • an aliquot of the reaction mixture (ca. 5 mL) is quenched with 25% aqueous sodium bisulfite (ca. 15 mL).
  • a portion of resulting slurry is filtered and submitted for GC analysis to check the progress of the reaction.
  • reaction mixture is quenched by slow (over 40 min) addition of cooled (ca. 0°C) 25% aqueous NaHSO 3 (60 L). The temperature of the reaction mixture is allowed to reach 4°C during the quench.
  • CELITE® (ca. 2.5 kg) is then slurried in acetone (8 kg) and added to the dark brown reaction mixture. The resulting slurry is aged at ambient temperature to obtain light tan slurry. The slurry is filtered, and the filter cake is washed with acetone (3 x 39 kg). The combined filtrate is concentrated by vacuum distillation (vacuum approximately 24 inches of Hg (ca. 810 mbar); max pot temperature is 32°C) to remove the acetone.
  • the aqueous concentrate is extracted with EtOAc (3 x 27 kg), and the combined organic extracts were washed with water (25 L). The organic phase is then concentrated by atmospheric distillation and EtOAc is replaced with toluene. The volume of the batch is adjusted to ca. 20 L. Heptane (62 kg) is added and the batch cooled to ca. 27° C to initiate crystallization. The batch is then cooled to -10° C. After aging overnight at -10 °C, the product is filtered, washed with 10% toluene in heptane and dried at 50 °C under vacuum to afford 6.91 kg (59.5%) of VI (CA RN 81997-76-4) as a white crystalline solid.
  • Steps 1 & 2 - A dry, clean vessel was charged with VI (6.0 kg), isopropyl acetate (28.0 kg), MeCN (3.8 kg) and TEA (5.4 kg). The mixture was cooled to 5 - 10 °C, and thionyl chloride (3.2 kg) was added slowly while cooling the solution to maintain the temperature below 20 °C. The mixture was stirred until no starting material was left (GC analysis). The reaction was typically complete within 30 min after addition is complete. To the mixture was added water (9 kg) and after stirring, the mixture was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a mixture of water (8 kg) and saturated NaHCO 3 (4 kg) solution.
  • Step 3 To the concentrated oil from step 2 containing VIII was added TEA (2.34 kg) and TEA-trihydrofluoride (1.63 kg). The mixture was heated to 85°C for 2 h. The batch was sampled to monitor the progress of the reaction by GC. After the reaction was complete conc. HCl (2.35 kg) was added to the mixture and the resulting mixture heated to ca. 90° C (small amount of distillate collected). The reaction mixture was stirred at ca. 90° C for 30 min and then saturated aqueous BaCl 2 solution (18.8 kg) was added. The resulting suspension was stirred at about 90°C for 4 h.
  • the resulting mixture was then azeotropically dried under a vacuum (9-10 inches of Hg) by adding slowly n-propanol (119 kg) while distilling off the azeotropic mixture (internal batch temperature ca. 85-90°C).
  • n-propanol 119 kg
  • toluene 33 kg
  • vacuum distillation was continued to distill off residual n-propanol (and traces of water) to a minimum volume to afford X.
  • Step 4 To the residue from step 3 containing X was added MeCN (35 kg) and ca. 15 L was distilled out under atmospheric pressure. The reaction mixture was cooled to ca. 10°C and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 40°C. The batch was aged at ca. 20°C and the progress of the benzoylation is monitored by HPLC. After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE® pad (using a nutsche filter) to remove inorganic salts.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
EP07839369.1A 2006-10-10 2007-10-05 Preparation of nucleosides ribofuranosyl pyrimidines Active EP2084174B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PL07839369T PL2084174T3 (pl) 2006-10-10 2007-10-05 Sposób otrzymywania nukleozydów rybofuranozylopirymidynowych
SI200731311T SI2084174T1 (sl) 2006-10-10 2007-10-05 Priprava nukleozidov ribofuranozil pririmidinov
CY20131100912T CY1114666T1 (el) 2006-10-10 2013-10-16 Παρασκευη νουκλεοσιδιων ριβοφουρανοζυλο πυριμιδινων

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85096206P 2006-10-10 2006-10-10
PCT/US2007/021548 WO2008045419A1 (en) 2006-10-10 2007-10-05 Preparation of nucleosides ribofuranosyl pyrimidines

Publications (2)

Publication Number Publication Date
EP2084174A1 EP2084174A1 (en) 2009-08-05
EP2084174B1 true EP2084174B1 (en) 2013-07-31

Family

ID=39111500

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07839369.1A Active EP2084174B1 (en) 2006-10-10 2007-10-05 Preparation of nucleosides ribofuranosyl pyrimidines

Country Status (18)

Country Link
US (2) US8912321B2 (https=)
EP (1) EP2084174B1 (https=)
JP (1) JP5252459B2 (https=)
KR (1) KR101057239B1 (https=)
CN (1) CN101600725B (https=)
AU (1) AU2007307057B2 (https=)
BR (1) BRPI0719174A2 (https=)
CA (1) CA2666098C (https=)
DK (1) DK2084174T3 (https=)
ES (1) ES2429290T3 (https=)
GT (1) GT200900080A (https=)
IL (1) IL198086A (https=)
MX (1) MX2009003795A (https=)
PL (1) PL2084174T3 (https=)
PT (1) PT2084174E (https=)
RU (1) RU2421461C2 (https=)
SI (1) SI2084174T1 (https=)
WO (1) WO2008045419A1 (https=)

Families Citing this family (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
HUE033832T2 (en) 2002-11-15 2018-01-29 Idenix Pharmaceuticals Llc 2'-methyl nucleosides in combination with interferon and Flaviviridae mutation
EP2345657A1 (en) 2003-05-30 2011-07-20 Pharmasset, Inc. Modified fluorinated nucleoside analogues
AU2005285045B2 (en) * 2004-09-14 2011-10-13 Gilead Sciences, Inc. Preparation of 2'fluoro-2'- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
ES2381982T3 (es) 2004-11-16 2012-06-04 Thomson Licensing Método de simulación del grano de película basado en coeficientes de transformación previamente generados por ordenador
BRPI0517828A (pt) 2004-11-16 2008-10-21 Thomson Licensing inserção de mensagens sei de grão de filme para uma simulação exata em bits em um sistema de vìdeo
ES2739452T3 (es) 2004-11-17 2020-01-31 Interdigital Vc Holdings Inc Método de simulación de grano de película con precisión de bits basado en coeficientes transformados calculados previamente
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US10715834B2 (en) 2007-05-10 2020-07-14 Interdigital Vc Holdings, Inc. Film grain simulation based on pre-computed transform coefficients
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
PT2376088T (pt) 2008-12-23 2017-05-02 Gilead Pharmasset Llc Fosforamidatos de nucleósidos de 2-amino-purina 6-osubstituída
SG194404A1 (en) * 2008-12-23 2013-11-29 Gilead Pharmasset Llc Synthesis of purine nucleosides
KR20110098849A (ko) 2008-12-23 2011-09-01 파마셋 인코포레이티드 뉴클레오시드 유사체
TWI598358B (zh) 2009-05-20 2017-09-11 基利法瑪席特有限責任公司 核苷磷醯胺
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
UY33312A (es) 2010-03-31 2011-10-31 Pharmasset Inc Fosforamidato de nucleosido de purina
PL3290428T3 (pl) 2010-03-31 2022-02-07 Gilead Pharmasset Llc Tabletka zawierająca krystaliczny (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropirymidyn-1(2H)-ylo)-4-fluoro-3-hydroksy-4-metylotetrahydrofuran-2-ylo)metoksy)(fenoksy)fosforylo)amino)propanian izopropylu
PT2609923T (pt) 2010-03-31 2017-08-30 Gilead Pharmasset Llc Processo para a cristalização de 2-(((s)- (perfluorofenoxi)(fenoxi)fosforil)amino)propanoato de (s)-isopropilo
JP5716500B2 (ja) 2010-06-03 2015-05-13 セントラル硝子株式会社 （２Ｒ）−２−フルオロ−２−Ｃ−メチル−Ｄ−リボノ−γ−ラクトン類前駆体の製造方法
AU2011336632B2 (en) 2010-11-30 2015-09-03 Gilead Pharmasset Llc Compounds
EP2691409B1 (en) 2011-03-31 2018-02-21 Idenix Pharmaceuticals LLC. Compounds and pharmaceutical compositions for the treatment of viral infections
TW201329096A (zh) 2011-09-12 2013-07-16 Idenix Pharmaceuticals Inc 經取代羰氧基甲基磷酸醯胺化合物及用於治療病毒感染之藥學組成物
PL2709613T5 (pl) 2011-09-16 2020-12-14 Gilead Pharmasset Llc Metody leczenia hcv
US8507460B2 (en) 2011-10-14 2013-08-13 Idenix Pharmaceuticals, Inc. Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
SE1450131A1 (sv) 2011-10-21 2014-05-07 Abbvie Inc DAA-kombinationsbehandling (t.ex. med ABT-072 eller ABT-333)för användning vid behandling av HCV
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
DE112012002748T5 (de) 2011-10-21 2014-07-31 Abbvie Inc. Verfahren zur Behandlung von HCV umfassend mindestens zwei direkt wirkende antivirale Wirkstoffe, Ribavirin aber nicht Interferon
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
CA2873315A1 (en) 2012-05-22 2013-11-28 Idenix Pharamaceuticals, Inc. D-amino acid compounds for liver disease
WO2013177188A1 (en) 2012-05-22 2013-11-28 Idenix Pharmaceuticals, Inc. 3',5'-cyclic phosphoramidate prodrugs for hcv infection
US9296778B2 (en) 2012-05-22 2016-03-29 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphate prodrugs for HCV infection
SG11201407336PA (en) 2012-05-25 2015-03-30 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
CN104379591A (zh) 2012-05-29 2015-02-25 弗·哈夫曼-拉罗切有限公司 用于制备2-脱氧-2-氟-2-甲基-d-呋喃核糖基核苷化合物的方法
CN103450148B (zh) * 2012-06-04 2018-06-12 浙江九洲药业股份有限公司 一种五元环硫酸酯化合物的合成方法
WO2014052638A1 (en) 2012-09-27 2014-04-03 Idenix Pharmaceuticals, Inc. Esters and malonates of sate prodrugs
KR102001280B1 (ko) 2012-10-08 2019-07-17 아이데닉스 파마슈티칼스 엘엘씨 Hcv 감염에 대한 2'-클로로 뉴클레오시드 유사체
CN103724301A (zh) * 2012-10-10 2014-04-16 上海特化医药科技有限公司 (2r)-2-脱氧-2,2-二取代-1,4-核糖内酯及其制备方法和用途
WO2014066239A1 (en) 2012-10-22 2014-05-01 Idenix Pharmaceuticals, Inc. 2',4'-bridged nucleosides for hcv infection
EP2935304A1 (en) 2012-12-19 2015-10-28 IDENIX Pharmaceuticals, Inc. 4'-fluoro nucleosides for the treatment of hcv
CN103012386B (zh) * 2012-12-26 2015-04-01 浙江普洛得邦制药有限公司 一种五元环状硫酸酯的制备方法
PT2950786T (pt) 2013-01-31 2020-03-03 Gilead Pharmasset Llc Formulação de combinação de dois compostos antivirais
US10034893B2 (en) 2013-02-01 2018-07-31 Enanta Pharmaceuticals, Inc. 5, 6-D2 uridine nucleoside/tide derivatives
US9309275B2 (en) 2013-03-04 2016-04-12 Idenix Pharmaceuticals Llc 3′-deoxy nucleosides for the treatment of HCV
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
WO2014160484A1 (en) 2013-03-13 2014-10-02 Idenix Pharmaceuticals, Inc. Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv
EP2981542B1 (en) 2013-04-01 2021-09-15 Idenix Pharmaceuticals LLC 2',4'-fluoro nucleosides for the treatment of hcv
US10005779B2 (en) 2013-06-05 2018-06-26 Idenix Pharmaceuticals Llc 1′,4′-thio nucleosides for the treatment of HCV
WO2015017713A1 (en) 2013-08-01 2015-02-05 Idenix Pharmaceuticals, Inc. D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
EA201690473A1 (ru) 2013-08-27 2017-03-31 ГАЙЛИД ФАРМАССЕТ ЭлЭлСи Комбинированный состав двух противовирусных соединений
CN104447923B (zh) * 2013-09-23 2018-03-30 中国药科大学 2’‑脱氧‑2’‑氟‑2’‑甲基核苷衍生物及其制备方法与在制药中的用途
WO2015161137A1 (en) 2014-04-16 2015-10-22 Idenix Pharmaceuticals, Inc. 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv
US9675632B2 (en) 2014-08-26 2017-06-13 Enanta Pharmaceuticals, Inc. Nucleoside and nucleotide derivatives
WO2016042576A1 (en) 2014-09-16 2016-03-24 Cadila Healthcare Limited Co-crystal of sofosbuvir and amino acid and process for preparation thereof
CN104744539A (zh) * 2014-09-19 2015-07-01 上海皓元生物医药科技有限公司 一种(2’r)-2’-脱氧-2’-氟-2’-甲基脲苷的合成方法
CN104327138B (zh) * 2014-10-21 2017-05-10 齐鲁制药有限公司 Psi‑7977中间体化合物的制备方法
WO2016073756A1 (en) 2014-11-06 2016-05-12 Enanta Pharmaceuticals, Inc. Deuterated nucleoside/tide derivatives
US9732110B2 (en) 2014-12-05 2017-08-15 Enanta Pharmaceuticals, Inc. Nucleoside and nucleotide derivatives
CN104610404B (zh) * 2015-01-16 2016-04-06 南通常佑药业科技有限公司 一种呋喃核糖磷酸酯衍生物的制备方法
CA3182565A1 (en) 2015-03-06 2016-09-15 Atea Pharmaceuticals, Inc. .beta.-d-2'-deoxy-2'-.alpha.-fluoro-2'-.beta.-c-substituted-2-modified-n6-substituted purine nucleotides for hcv treatment
CN104829672B (zh) * 2015-05-19 2018-03-13 江苏福瑞生物医药有限公司 一种药物中间体的合成方法
CN105061535A (zh) * 2015-09-02 2015-11-18 江苏科本医药化学有限公司 一种索非布韦中间体的合成方法
CN106554333B (zh) * 2015-09-29 2018-11-30 江苏福瑞生物医药有限公司 一种药物中间体的合成方法
CN106608896B (zh) * 2015-10-26 2019-08-27 江苏福瑞康泰药业有限公司 一种药物中间体的合成方法
CN105418547A (zh) * 2015-11-17 2016-03-23 海门慧聚药业有限公司 索非布韦关键中间体的制备
CN105503983B (zh) * 2015-12-17 2019-06-28 江苏阿尔法药业有限公司 索菲布韦中间体及其衍生物的制备方法
CN105566422B (zh) * 2015-12-29 2019-06-25 江苏阿尔法药业有限公司 索菲布韦中间体或其衍生物的制备方法
EA201892448A1 (ru) 2016-04-28 2019-06-28 Эмори Юниверсити Алкинсодержащие нуклеотидные и нуклеозидные терапевтические композиции и связанные с ними способы применения
US10711029B2 (en) 2016-07-14 2020-07-14 Atea Pharmaceuticals, Inc. Beta-d-2′-deoxy-2′-alpha-fluoro-2′-beta-c-substituted-4′fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection
US10239910B2 (en) 2016-07-20 2019-03-26 Optimus Drugs (P) Limited Process for the preparation of sofosbuvir
DK3512863T3 (da) 2016-09-07 2022-03-07 Atea Pharmaceuticals Inc 2¿-substituerede-N6-substituerede purinnukleotider til behandling af RNA-virus
CN115477679A (zh) 2017-02-01 2022-12-16 阿堤亚制药公司 用于治疗丙型肝炎病毒的核苷酸半硫酸盐
CN106810515A (zh) * 2017-02-06 2017-06-09 抚州市星辰药业有限公司 一种合成索非布韦的中间体化合物及其合成方法
CN109422789A (zh) * 2017-08-28 2019-03-05 常州制药厂有限公司 一种索非布韦的制备工艺改进方法
EP3773753A4 (en) 2018-04-10 2021-12-22 ATEA Pharmaceuticals, Inc. TREATMENT OF PATIENTS INFECTED WITH THE HEPATITIS C VIRUS WITH CIRRHOSIS
CN108675984A (zh) * 2018-06-22 2018-10-19 江苏阿尔法药业有限公司 索非布韦中间体的制备方法
CN111606961A (zh) * 2019-02-26 2020-09-01 顾世海 一种(2’r)-2’-脱氧-2’-氟-2’-甲基脲苷的工艺生产方法
CN111040010A (zh) * 2019-12-23 2020-04-21 上海红蓝医药科技有限公司 一种索非布韦中间体的合成方法
US10874687B1 (en) 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
KR20240022574A (ko) 2021-06-17 2024-02-20 아테아 파마슈티컬즈, 인크. 유리한 항-hcv 조합 요법

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR850002973A (ko) * 1983-10-03 1985-05-28 구라바야시 이꾸시로 시티딘 유도체의 제조방법
JP2559917B2 (ja) * 1990-06-15 1996-12-04 三共株式会社 ピリミジンヌクレオシド誘導体
US5637688A (en) * 1994-12-13 1997-06-10 Eli Lilly And Company Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride
KR100719606B1 (ko) * 1998-02-25 2007-05-17 에모리 유니버시티 2'-플루오로뉴클레오사이드
SK1512002A3 (en) 1999-07-30 2002-11-06 Abbott Gmbh & Co Kg 2-pyrazolin-5-ones
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
KR20080021797A (ko) 2000-05-26 2008-03-07 이데닉스(케이만)리미티드 플라비바이러스 및 페스티바이러스의 치료방법 및 조성물
US7105499B2 (en) * 2001-01-22 2006-09-12 Merck & Co., Inc. Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase
WO2002057425A2 (en) 2001-01-22 2002-07-25 Merck & Co., Inc. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
AU2002330154A1 (en) 2001-09-28 2003-04-07 Centre National De La Recherche Scientifique Methods and compositions for treating hepatitis c virus using 4'-modified nucleosides
BR0312271A (pt) 2002-06-28 2007-11-06 Idenix Cayman Ltd compostos, composições e seus usos para o tratamento de infecções por flaviviridae
PL374781A1 (en) 2002-06-28 2005-10-31 Idenix (Cayman) Limited 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections
US7608600B2 (en) * 2002-06-28 2009-10-27 Idenix Pharmaceuticals, Inc. Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections
HUE033832T2 (en) 2002-11-15 2018-01-29 Idenix Pharmaceuticals Llc 2'-methyl nucleosides in combination with interferon and Flaviviridae mutation
TWI332507B (en) * 2002-11-19 2010-11-01 Hoffmann La Roche Antiviral nucleoside derivatives
EP2345657A1 (en) 2003-05-30 2011-07-20 Pharmasset, Inc. Modified fluorinated nucleoside analogues
EP1658302B1 (en) 2003-07-25 2010-08-25 IDENIX Pharmaceuticals, Inc. Purine nucleoside analogues for treating diseases caused by flaviviridae including hepatitis c
CN1863813B (zh) * 2003-08-27 2011-03-30 生物区科学管理控股有限公司 作为治疗剂的三环核苷或核苷酸
EP1741716B8 (en) * 2004-04-30 2012-02-22 Daiichi Sankyo Company, Limited Process for producing pentacyclic taxane
AU2005267051B2 (en) 2004-07-21 2011-07-14 Gilead Sciences, Inc. Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
AU2005285045B2 (en) * 2004-09-14 2011-10-13 Gilead Sciences, Inc. Preparation of 2'fluoro-2'- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives

Also Published As

Publication number Publication date
IL198086A (en) 2012-03-29
WO2008045419A1 (en) 2008-04-17
PL2084174T3 (pl) 2013-12-31
CN101600725A (zh) 2009-12-09
JP5252459B2 (ja) 2013-07-31
CA2666098C (en) 2012-09-25
RU2421461C2 (ru) 2011-06-20
AU2007307057A1 (en) 2008-04-17
AU2007307057B2 (en) 2011-09-15
US20080139802A1 (en) 2008-06-12
JP2010505954A (ja) 2010-02-25
KR101057239B1 (ko) 2011-08-16
SI2084174T1 (sl) 2013-10-30
HK1133889A1 (en) 2010-04-09
BRPI0719174A2 (pt) 2017-06-13
RU2009117396A (ru) 2010-11-20
DK2084174T3 (da) 2013-11-04
US8912321B2 (en) 2014-12-16
CN101600725B (zh) 2014-11-26
GT200900080A (es) 2012-04-10
ES2429290T3 (es) 2013-11-14
IL198086A0 (en) 2009-12-24
MX2009003795A (es) 2009-06-18
EP2084174A1 (en) 2009-08-05
KR20090060460A (ko) 2009-06-12
US20100056770A1 (en) 2010-03-04
PT2084174E (pt) 2013-10-08
CA2666098A1 (en) 2008-04-17

Similar Documents

Publication Publication Date Title
EP2084174B1 (en) Preparation of nucleosides ribofuranosyl pyrimidines
Mansuri et al. Preparation of 1-(2, 3-dideoxy-. beta.-D-glycero-pent-2-enofuranosyl) thymine (d4T) and 2', 3'-dideoxyadenosine (ddA): general methods for the synthesis of 2', 3'-olefinic and 2', 3'-dideoxy nucleoside analogs active against HIV
JP2010505954A5 (https=)
EP0342203B1 (en) 2',3' dideoxyribofuranoxide derivatives
EP2855497B1 (en) Process for the preparation of 2-deoxy-2-fluoro-2-methyl-d-ribofuranosyl nucleoside compounds
WO2004084453A2 (en) METHODS OF MANUFACTURE OF 2'-DEOXY-β-L-NUCLEOSIDES
NZ247936A (en) Stereoselective anion glycosylation process for the preparation of a beta anomer enriched nucleoside
US7365188B2 (en) Process for producing N4-Acyl-5′-deoxy-5-fluorocytidine
CN86101400A (zh) 胞嘧啶核苷的制备
CN102171195B (zh) 合成地西他滨
JP2009526782A (ja) ゲムシタビンおよび関連中間体の製造方法
HK1133889B (en) Preparation of nucleosides ribofuranosyl pyrimidines
US6897302B2 (en) Method for synthesizing β-L-5-fluoro-2′,3′-dideoxy-2′,3′-didehydrocytidine (β-L-FD4C)
Richardson et al. Synthesis and properties of psico-nucleosides
EP1812457A1 (en) STEREOSELECTIVE SYNTHESIS OF ß-NUCLEOSIDES
WO2007070804A2 (en) Process for preparing gemcitabine and associated intermediates

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090507

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20091021

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1133889

Country of ref document: HK

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: GILEAD PHARMASSET LLC

Owner name: F. HOFFMANN-LA ROCHE AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: GILEAD PHARMASSET LLC

Owner name: F. HOFFMANN-LA ROCHE AG

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 624598

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130815

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: BOVARD AG, CH

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602007032035

Country of ref document: DE

Effective date: 20130926

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20130930

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20131028

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2429290

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20131114

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1133889

Country of ref document: HK

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20130402011

Country of ref document: GR

Effective date: 20131015

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E008522

Country of ref document: EE

Effective date: 20131010

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131130

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 15291

Country of ref document: SK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20140502

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602007032035

Country of ref document: DE

Effective date: 20140502

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E020520

Country of ref document: HU

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: EE

Payment date: 20180919

Year of fee payment: 12

Ref country code: MC

Payment date: 20180925

Year of fee payment: 12

Ref country code: RO

Payment date: 20180920

Year of fee payment: 12

Ref country code: LT

Payment date: 20180918

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FI

Payment date: 20181029

Year of fee payment: 12

Ref country code: MT

Payment date: 20180919

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LV

Payment date: 20180926

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20180921

Year of fee payment: 12

REG Reference to a national code

Ref country code: FI

Ref legal event code: MAE

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E008522

Country of ref document: EE

Effective date: 20191031

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20191031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191031

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20191005

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191031

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191005

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191005

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191005

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191005

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191005

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200531

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191005

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191006

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20191031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20191005

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20250911

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20250912

Year of fee payment: 19

Ref country code: NL

Payment date: 20250912

Year of fee payment: 19

Ref country code: IT

Payment date: 20250922

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20250917

Year of fee payment: 19

Ref country code: GB

Payment date: 20250904

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20250908

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20250910

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20250909

Year of fee payment: 19

Ref country code: CZ

Payment date: 20250923

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SK

Payment date: 20250912

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SI

Payment date: 20250915

Year of fee payment: 19

REG Reference to a national code

Ref country code: CH

Ref legal event code: U11

Free format text: ST27 STATUS EVENT CODE: U-0-0-U10-U11 (AS PROVIDED BY THE NATIONAL OFFICE)

Effective date: 20251101

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20251003

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20250902

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20250925

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20251001

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20251101

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20251106

Year of fee payment: 19